DESCRIPTION (Applicant's abstract): We have discovered novel inhibitory neural pathways which interact with excitatory neural reflexes to regulate tracheobronchial mucociliary function. We propose that impaired tracheobronchial mucociliary clearance results from activation of predominantly inhibitory reflexes. These neural reflexes, activated by ammonia and SO2 regulate the components of the mucociliary transport system, namely ciliary beat frequency and airway secretory output. Inhalation of acidic irritants, such as SO2, primarily activate inhibitory neural pathways that suppress ciliary activity yet via cause a highly viscous mucus with an large relaxation time. In concert, these responses result in defective mucociliary transport and mucus accumulation in the airways. To delineate the proposed inhibitory neural pathways and their roles in the regulation of the mucociliary transport system, we will use a canine model in which the vagosympathetic trunks are exteriorized in skin tubes. Tracheal mucus velocity, TMV, and bronchial mucociliary clearance, BMC, will be measured using radioaerosol techniques. Airway secretory output, ASO, will be measured using a secretion collecting endotracheal tube and the rheological properties measured using rotational magnetic microrheometry. Ciliary beat frequency, CBF, will be measured in the trachea using heterodyne laser light scattering. SO2 will be used to activate the inhibitory reflex. We will demonstrate two inhibitory reflexes, one that traverses the vagosympathetic trunks and the other the sympathetic ganglia. We will identify the dominant ganglionic and efferent inhibitory and excitatory neural transmitters by cooling the vagosympathetic trunks to 0 degrees C, and by judicious local administration of general and specific inhibitors of ganglionic and receptor function. We will show the causal relationships between the neural transmission of the proposed inhibitory reflexes, and the suppression of CBF, changes in ASO and mucus viscosity and relaxation time. Through the derivation of the airway fluid depth, AFD, and the distance mucus is transported/ciliary beat, we will show the extent to which changes in CBF and/or airway secretory output and viscosity and relaxation time contribute to impaired mucociliary transport. Through the elucidation of the neural regulation of normal mucociliary function and the mechanisms underlying perturbations in this regulation that lead to abnormal mucociliary clearance, we will ascertain new potential pathogenic mechanisms contributing to the pathogenesis of diseases of the airways such as bronchitis, asthma and cystic fibrosis. Also possible sites and agents for therapeutic intervention will be identified.